Anticholinesterase agents are used as topical agents for the treatment of ophthalmological conditions such as glaucoma; of certain muscle disorders, such as myasthenia gravis and as insecticides. For example, DFP (diisopropyl-phosphorofluoridate) and O,O-diethyl-S-(2-(N,N,N-trimethylammonio)ethyl)-phosphorothiolate iodide (Phospholine) are used for the relief of intraoccular pressure in glaucoma. Tetram (O,O-diethyl S-(2-(N,N-diethylamino)ethyl)-phosphorothiolate is known as powerful insecticide. Carbamates such as physostygmine and pyridostigmine are useful in the treatment of myasthenia gravis, (Flake New Eng. J.Med.288, 27 (1973)).
All the above compounds have the drawback of having a comparatively high toxicity towards mammals. Furthermore, some of the compounds used as drugs have a comparatively brief duration of activity, and this is especially pronounced with the carbamates. The side-effects inherent to such active anticholinesterase (AcChE) inhibitors reduces their wide applicability.
The LD.sub.50 of phospholine to mice is about 0.13 mg/kg (s.c.) and that of neostigmine is 0.42 mg/kg (mice s.c.). DFP is somewhat less toxic, the LD.sub.50 towards mice i.p., being 4 mg/kg. It has been shown recently that AcChE inhibited by 1,3,2-dioxaphosphorinane-2-oxide derivatives of the formula ##STR3## wherein X designates --F, --Cl or p-nitrophenyl, undergoes spontaneous reactivation with t.sub.1/2 = 12 minutes at pH 7.0 (Ashani et al, Biochem.11, 3518 (1972)). These compounds are characterized by a low toxicity towards mammals, this being above 100 mg/kg for mice, s.c. It has also been established that phosphorothiolates with leaving groups of the formula (alkyl).sub.2 --N--CH.sub.2 --CH.sub.2 S-- ae excellent inhibitors of AcChE, (Maglothin et al, Biochem.,13, 3520 (1974)).